1.NAME OF THE MEDICINAL PRODUCT
Busulfan 2 mg tablets Taj Pharma
- QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 2 mg tablet contains 2 mg of the active substance busulfan
For the full list of excipients, see section 6.1.
- PHARMACEUTICAL FORM
Busulfan 2 mg tablets are white, film-coated, round biconvex tablets engraved ?GX EF3? on one side and ?M? on the other.
- CLINICAL PARTICULARS
4.1 Therapeutic indications
Busulfan is indicated as conditioning treatment prior to haemopoietic progenitor cell transplantation in patients when the combination of high-dose busulfan and cyclophosphamide is considered the best available option.
Busulfan is indicated for the palliative treatment of the chronic phase of chronic myeloid leukaemia.
Busulfan is effective in producing prolonged remission in polycythaemia vera, particularly in cases with marked thrombocytosis.
Busulfan may be useful in selected cases of essential thrombocythaemia and myelofibrosis.
4.2 Posology and method of administration
The bioavailability of oral Busulfan shows large intra-individual variations ranging from 47% to 103% (mean 80%) in adults and from 22% to 120% (mean 68%) in children (see section 5.2).
There are other formulations available which may be more suitable for paediatric patients.
Busulfan tablets are usually given in courses or administered continuously. The dose must be adjusted for the individual patient under close clinical and haematological control. Should a patient require an average daily dose of less than the content of the available Busulfan tablets, this can be achieved by introducing one or more busulfan free days between treatment days. The tablets should not be divided (see section 6.6).
Dosing based on body surface area or adjusted ideal body weight should be considered in the obese (see section 5.2).
The relevant literature should be consulted for full details of treatment schedules.
Conditioning prior to haemopoietic progenitor cell transplantation
When bulsulfan is used as a conditioning treatment prior to haemopoietic progenitor cell transplantation, drug level monitoring is recommended.
The recommended dose of busulfan in adult patients is 1 mg/kg every 6 hours for four days, starting seven days prior to transplantation. 60 mg/kg per day of cyclophosphamide is usually given for two days commencing 24 h after the final dose of Busulfan (see section 4.4 and 4.5).
The conventional dosage plan for conditioning before haemopoietic stem cell transplantation is 30 to 37.5 mg/m2?every 6 hours for 4 days, starting seven days prior to transplantation. The dosing of cyclophosphamide is the same as for adults.
Chronic myeloid leukaemia
Induction in adults
Treatment is usually initiated as soon as the condition is diagnosed. The dose is 0.06 mg/kg/day, with an initial daily maximum of 4 mg, which may be given as a single dose.
There is individual variation in the response to Busulfan and in a small proportion of patients the bone marrow may be extremely sensitive (see section 4.4).
The blood count must be monitored at least weekly during the induction phase and it may be helpful to plot counts on semilog graph paper.
The dose should be increased only if the response is inadequate after three weeks.
Treatment should be continued until the total leucocyte count has fallen to between 15 and 25 x 109?per litre (typically 12 to 20 weeks). Treatment may then be interrupted, following which a further fall in the leucocyte count may occur over the next two weeks. Continued treatment at the induction dose after this point or following depression of the platelet count to below 100 x 109per litre is associated with a significant risk of prolonged and possibly irreversible bone marrow aplasia.
Maintenance in adults
Control of the leukaemia may be achieved for long periods without further Busulfan treatment; further courses are usually given when the leucocyte count rises to 50 x 109?per litre, or symptoms return.
Some clinicians prefer to give continuous maintenance therapy. Continuous treatment is more practical when the duration of unmaintained remissions is short.
The aim is to maintain a leucocyte count of 10 to 15 x 109?per litre and blood counts must be performed at least every 4 weeks. The usual maintenance dosage is on average 0.5 to 2 mg/day, but individual requirements may be much less. Should a patient require an average daily dose of less than the content of one tablet, the maintenance dose may be adjusted by introducing one or more Busulfan free days between treatment days.
Note: Lower doses of Busulfan should be used if it is administered in conjunction with other cytotoxic agents (see section 4.5 and 4.8).
Chronic myeloid leukaemia is very rare in the paediatric age group. Busulfan may be used to treat Philadelphia chromosome positive (Ph’ positive) disease, but the Ph’ negative juvenile variant responds poorly.
The usual dose is 4 to 6 mg daily, continued for 4 to 6 weeks, with careful monitoring of the blood count, particularly the platelet count.
Further courses are given when relapse occurs; alternatively, maintenance therapy may be given using approximately half the induction dose.
If the polycythaemia is controlled primarily by venesection, short courses of Busulfan may be given solely to control the platelet count.
The usual initial dose is 2 to 4 mg daily.
Very careful haematological control is required because of the extreme sensitivity of the bone marrow in this condition.
The usual dose is 2 to 4 mg per day.
Treatment should be interrupted if the total leucocyte count falls below 5 x 109?per litre or the platelet count below 500 x 109?per litre.
?Busulfan should not be used in patients whose disease has demonstrated resistance to busulfan.
Busulfan should not be given to patients who have previously suffered a hypersensitivity reaction to the busulfan or any other component of the preparation.
4.4 Special Warnings and precautions for use
Busulfan is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Busulfan should be discontinued if lung toxicity develops (see section 4.8).
Busulfan should not generally be given in conjunction with or soon after radiotherapy.
Busulfan is ineffective once blast transformation has occurred.
If anaesthesia is required in patients with possible pulmonary toxicity, the concentration of inspired oxygen should be kept as low as safely as possible and careful attention given to post-operative respiratory care.
Hyperuricaemia and/or hyperuricosuria are not uncommon in patients with chronic myeloid leukaemia and should be corrected before starting treatment with Busulfan. During treatment, hyperuricaemia and the risk of uric acid nephropathy should be prevented by adequate prophylaxis, including adequate hydration and the use of allopurinol.
Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients. However, caution is recommended.
Busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when busulfan is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment.
The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Conventional dose Treatment
Patients who are concurrently treated with the conventional dose of busulfan and itraconazole or metronidazole should be closely monitored for signs of busulfan toxicity. At concomitant use of these agents with busulfan weekly blood counts are recommended (see section 4.5).
Careful attention must be paid to monitoring the blood counts throughout treatment to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia (see section 4.8).
Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busulfan. Patients who have received prior radiation therapy, for three or more cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of developing hepatic veno-occlusive disease (see section 4.8).
High-dose Treatment (used for Haemopoetic Stem Cell Transplantation)
If high-dose Busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy, preferably with a benzodiazepine rather than phenytoin.
Concomitant administration of itraconazole or metronidazole with high-dose busulfan has been reported to be associated with an increased risk of busulfan toxicity (see section 4.5). Co-administration of metronidazole and high-dose busulfan is not recommended. Co-administration of itraconazole with high-dose busulfan should be at the discretion of the prescribing physician and should be based on a risk/benefit assessment.
A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high-dose Busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for > 24 hours after the last dose of Busulfan.
Safe Handling of Busulfan Tablets
See section 6.6
Busulfan is genotoxic in non-clinical studies (see section 5.3).
Various chromosome aberrations have been noted in cells from patients receiving busulfan.
On the basis of human studies, Busulfan was considered by the International Agency for Research on cancer to show sufficient evidence for carcinogenicity. The World Health Association has concluded that there is a causal relationship between Busulfan exposure and cancer.
Widespread epithelial dysplasia has been observed in patients treated with long-term Busulfan, with some of the changes resembling precancerous lesions.
A number of malignant tumours have been reported in patients who have received Busulfan treatment.
The evidence is growing that Busulfan, in common with other alkylating agents, is leukaemogenic. In a controlled prospective study in which 2 years’ Busulfan treatment was given as an adjuvant to surgery for lung cancer, long-term follow-up showed an increased incidence of acute leukaemia compared with the placebo-treated group. The incidence of solid tumours was not increased.
Although acute leukaemia is probably part of the natural history of polycythaemia vera, prolonged alkylating agent therapy may increase the incidence.
Very careful consideration should be given to the use of busulfan for the treatment of polycythaemia vera and essential thrombocythaemia in view of the drug’s carcinogenic potential. The use of busulfan for these indications should be avoided in younger or asymptomatic patients. If the drug is considered necessary treatment courses should be kept as short as possible.
4.5 Interaction with other medicinal products and other forms of interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).
The effects of other cytotoxics producing pulmonary toxicity may be additive.
The administration of phenytoin to patients receiving high-dose Busulfan may result in a decrease in the myeloblative effect.
In patients receiving high-dose busulfan it has been reported that co-administration of itraconazole decreases clearance of busulfan by approximately 20 % with corresponding increases in plasma busulfan levels. In combination with metronidazole (1200 mg, given as 400 mg three times daily) busulfan values are increased in approximately 80% (see section 4.4). Fluconazole had no effect on busulfan clearance. Consequently, high-dose Busulfan in combination with itraconazole or metronidazole is reported to be associated with an increased risk of busulfan toxicity (see section 4.4).
A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high-dose Busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for > 24 hours after the last dose of busulfan.
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination.
4.6 Fertility, Pregnancy and lactation
Busulfan can lead to suppression of ovarian function and amenorrhoea in women and suppression of spermatogenesis in men (see section 4.8 and 5.3).
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Busulfan.
The use of Busulfan should be avoided during pregnancy whenever possible. In animal studies (see section 5.3) it has the potential for teratogenic effects, whilst exposure during the latter half of pregnancy resulted in impairment of fertility in offspring. In every individual case the expected benefit of treatment to the mother must be weighed against the possible risk to the foetus.
A few cases of congenital abnormalities, not necessarily attributable to busulfan, have been reported and third trimester exposure may be associated with impaired intra-uterine growth. However, there have also been many reported cases of apparently normal children born after exposure to Busulfan in utero, even during the first trimester.
It is not known whether Busulfan or its metabolites are excreted in human breast milk. Mothers receiving Busulfan should not breast-feed their infants.
4.7 Effects on ability to drive and use machines
There are no data on the effect of Busulfan on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
4.8 Undesirable Effects
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The following convention has been utilised for the classification of frequency: Very common (? 1/10), common (? 1/100 and < 1/10), uncommon (? 1/1000 and < 1/100), rare (? 1/10,000 and < 1/1000), very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data).
The following table of adverse reactions originated from the use of busulfan, or busulfan in combination with other therapeutic agents.
|System organ class||Frequency||Side effects|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)||Common||Leukaemia secondary to oncology chemotherapy (see section 4.4)|
|Blood and lymphatic system disorders *||Very common||Dose-related bone marrow failure, manifesting as leukopenia and particularly thrombocytopenia|
|Nervous system disorders||Rare||At high-dose: convulsion (see section 4.4 and 4.5)|
|Very rare||Myasthenia gravis|
|Eye disorders||Rare||Lens disorder and cataract (which may be bilateral) corneal thinning (reported after bone marrow transplantation preceded by high-dose Busulfan treatment)|
|Cardiac disorders||Common||At high-dose: cardiac tamponade in patients with thalassaemia|
|Respiratory, thoracic and mediastinal disorders *||Very common||At high-dose: idiopathic pneumonia syndrome|
|Common||Interstitial lung disease following long term conventional dose use|
|Gastrointestinal disorders||Very common||At high-dose: nausea, vomiting, diarrhoea, mouth ulceration|
|Rare||At conventional dose: nausea, vomiting, diarrhoea, mouth ulceration, which may possibly be ameliorated by using divided doses. Dry mouth|
|Not known||Tooth hypoplasia|
|Hepatobiliary disorders *||Very common||At-high-dose: hyperbilirubinaemia, jaundice, venoocclusive liver disease (see section 4.4 and 4.5) and biliary fibrosis with hepatic atrophy and necrosis|
|Rare||Jaundice and abnormal hepatic function, at conventional dose. Biliary fibrosis|
|Skin and subcutaneous tissue disorders *||Common||Alopecia at high-dose. Skin hyperpigmentation (see also General disorders and administration site conditions)|
|Rare||Alopecia at conventional dose, skin reactions including urticaria, erythema multiforme, erythema nodosum, porphyrianon-acute, rash, dry skin and fragility of the skin with complete anhydrosis cheilosis, Sj?gren’s syndrome. An increased radiation skin injury in patients receiving radiotherapy soon after high-dose Busulfan|
|Renal and urinary disorders||Common||At high-dose: in combination with cyclophosphamide cystitis haemorrhagic|
|Reproductive system and breast disorders *||Very common||Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at high-dose; severe and persistent ovarian failure, including failure to achieve puberty after administration to young girls and pre-adolescents at high-dose. Male infertility, azoospermia and testicular atrophy in male patients receiving Busulfan|
|Uncommon||Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at conventional dose. In very rare cases, recovery of ovarian function has been reported with continuing treatment|
|General disorders and administration site conditions *||Rare||Dysplasia|
* Description of selected adverse events
Blood and lymphatic system disorders
Aplastic anaemia (sometimes irreversible) has been reported rarely, typically following long-term conventional doses and also high doses of Busulfan.
Respiratory, thoracic and mediastinal disorders
Pulmonary toxicity after either high or conventional dose treatment typically presents with non-specific non-productive cough, dyspnoea and hypoxia with evidence of abnormal pulmonary physiology. Other cytotoxic agents may cause additive lung toxicity (see section 4.5). It is possible that subsequent radiotherapy can augment subclinical lung injury caused by busulfan. Once pulmonary toxicity is established the prognosis is poor despite busulfan withdrawal and there is little evidence that corticosteroids are helpful.
Idiopathic pneumonia syndrome is a non-infectious diffuse pneumonia which usually occurs within three months of high-dose Busulfan conditioning prior to allogeneic or autologous haemopoietic transplant. Diffuse alveolar haemorrhage may also be detected in some cases after broncholavage. Chest X-rays or CT scans show diffuse or non-specific focal infiltrates and biopsy shows interstitial pneumonitis and diffuse alveolar damage and sometimes fibrosis.
Interstitial pneumonitis may occur following conventional dose use and lead to pulmonary fibrosis. This usually occurs after prolonged treatment over a number of years. The onset is usually insidious but may also be acute. Histological features include atypical changes of the alveolar and bronchiolar epithelium and the presence of giant cells with large hyperchromatic nuclei. The lung pathology may be complicated by superimposed infections. Pulmonary ossification and dystrophic calcification have also been reported.
Busulfan is not generally considered to be significantly hepatotoxic at normal therapeutic doses. However, retrospective review of postmortem reports of patients who had been treated with low-dose busulfan for at least two years for chronic myeloid leukaemia showed evidence of centrilobular sinusoidal fibrosis.
Skin and subcutaneous tissue disorders
Hyperpigmentation occurs, particularly in?those with a dark complexion. It is often most marked on the neck, upper trunk, nipples, abdomen and palmar creases. This may also occur as part of a clinical syndrome (see General disorders and administration site conditions).
Reproductive system and breast disorders
Studies of busulfan treatment in animals have shown reproductive toxicity (see section 5.3).
General disorders and administration site conditions
Clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting and hyperpigmentation of the skin) resembling adrenal insufficiency (Addison’s disease) but without biochemical evidence of adrenal suppression, mucous membrane hyperpigmentation or hair loss (see Skin and subcutaneous tissue disorders) has been seen in a few cases following prolonged Busulfan therapy. The syndrome has sometimes resolved when busulfan has been withdrawn.
Many histological and cytological changes have been observed in patients treated with busulfan, including widespread dysplasia affecting uterine cervical, bronchial and other epithelia. Most reports relate to long-term treatment but transient epithelial abnormalities have been observed following short-term, high-dose treatment.
The following table of adverse reactions originated from the intravenous use of busulfan in combination with cyclophosphamide or melphalan.
|System organ class||Frequency||Side effects|
|Immune system disorders||Very common||Hypersensitivity|
|Metabolism and nutrition disorders||Very common||Hyperglycaemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia|
|Psychiatric disorders||Very common||Anxiety, depression, insomnia|
|Uncommon||Delirium, nervousness, hallucination, agitation|
|Nervous system disorders||Very common||Headache, dizziness|
|Uncommon||Encephalopathy, cerebral haemorrhage|
|Cardiac disorders||Very common||Tachycardia|
|Common||Arrhythmia, atrial fibrillation, cardiomegaly, pericarditis|
|Uncommon||Ventricular extrasystoles, bradycardia|
|Vascular disorders||Very common||Hypertension, hypotension, thrombosis, vasodilation|
|Uncommon||Femoral artery thrombosis, capillary leak syndrome|
|Respiratory, thoracic and mediastinal disorders||Common||Hyperventilation, respiratory failure, asthma, atelectasis, pleural effusion|
|Gastrointestinal disorders||Very common||Abdominal pain, dyspepsia, ascites, constipation, anorectal discomfort|
|Common||Haematemesis, ileus, oesophagitis|
|Hepatobiliary disorders||Very common||Hepatomegaly|
|Musculoskeletal and connective tissue disorders||Very common||Myalgia, back pain, arthralgia|
|Renal and urinary disorders||Very common||Dysuria, oliguria|
|Common||Haematuria, moderate renal insufficiency|
|General disorders and administration site conditions||Very common||Chills, pyrexia, chest pain, oedema, general oedema, pain|
|Investigations||Very common||Weight increased, abnormal breath sounds, blood creatinine increased|
|Common||Blood urea increased, decreased ejection fraction|
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
Symptoms and signs
The acute dose-limiting toxicity of Busulfan in man is myelosuppression (see section 4.8).
The main effect of chronic overdose is bone marrow depression and pancytopenia.
There is no known antidote to Busulfan. Haemoialysis should be considered in the management of overdose as there is one report of successful haemodialysis of Busulfan.
Appropriate supportive treatment should be given during the period of haematological toxicity.
- PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Busulfan (1,4-butanediol dimethanesulfonate) is a bifunctional alkylating agent. Binding to DNA is believed to play a role in its mode of action and di-guanyl derivaties have been isolated but interstrand crosslinking has not been conclusively demonstrated.
The basis for the uniquely selective effect of busulfan on granulocytopoiesis is not fully understood. Although not curative, Busulfan is very effective in reducing the total granulocyte mass, relieving the symptoms of disease and improving the clinical state of the patient. Busulfan has been shown to be superior to splenic irradiation when judged by survival times and maintenance of haemoglobin levels and is as effective in controlling spleen size.
5.2 Pharmacokinetic properties
The bioavailability of oral Busulfan shows large intra-individual variations ranging from 47 % to 103 % (mean 80 %) in adults.
The area under the curve (AUC) and peak plasma concentrations (Cmax) of Busulfan have been shown to be linearly dose dependent. Following administration of a single 2 mg oral dose of Busulfan, the AUC and Cmax?of Busulfan were 125 ? 17 nanograms.h/ml and 28 ? 5 nanograms/ml respectively.
A lag time between Busulfan administration and detection in the plasma of up to 2 h has been reported.
Drug was assayed either using gas liquid chromatography with electron capture detection or by high-performance liquid chromatography (HPLC).
Following oral administration of high-dose Busulfan (1 mg/kg every 6 h for 4 days), AUC and Cmax?in adults are highly variable but have been reported to be 8260 nanograms.h/ml (range 2484 to 21090) and 1047 nanograms/ml (range 295 to 2558) respectively when measured by HPLC and 6135 nanograms.h/ml (range 3978 to 12304) and 1980 nanograms/ml (range 894 to 3800) respectively using gas chromatography.
Busulfan is reported to have a volume of distribution of 0.64 ? 0.12 L/kg in adults.
Busulfan given in high-doses has recently been shown to enter the cerebrospinal fluid (CSF) in concentrations comparable to those found in plasma, with a mean CSF:plasma ration of 1.3:1. The saliva:plasma distribution of Busulfan was 1.1:1.
The level of busulfan bound reversibly to plasma proteins has been variably reported to be insignificant or approximately 55 %. Irreversible binding of drug to blood cells and plasma proteins has been reported to be 47 % and 32 %, respectively.
Busulfan metabolism involves a reaction with glutathione, which occurs via the liver and is mediated by glutathione-S-transferase.
The urinary metabolites of busulfan have been identified as 3-hydroxysulpholane, tetrahydrothiophene 1-oxide and sulpholane, in patients treated with high-dose Busulfan. Very little busulfan is excreted unchanged in the urine.
Busulfan has a mean elimination half life of between 2.3 and 2.8 h. Adult patients have demonstrated a clearance of busulfan of 2.4 to 2.6 ml/min/kg. The elimination half life of busulfan has been reported to decrease upon repeat dosing suggesting that busulfan potentially increases its own metabolism.
Very little (1 to 2 %) busulfan is excreted unchanged in the urine.
Special Patient Populations
The bioavailability of oral busulfan shows large intra-individual variation ranging from 22 % to 120 % (mean 68 %) in children.
Plasma clearance is reported to be 2 to 4 times higher in children than in adults when receiving 1 mg/kg every 6 h for 4 days. Dosing children according to body surface area has been shown to give AUC and Cmax?values similar to those seen in adults. The area under the curve has been shown to be half that of adults in children under the age of 15 years and a quarter of that of adults in children under 3 years of age.
Busulfan is reported to have a volume of distribution of 1.15 ? 0.52 L/kg in children.
When busulfan is administered at a dose of 1 mg/kg every 6 h for 4 days, the CSF:plasma ratio has been shown to be 1.02:1. However, when administered at a dose of 37.5 mg/m2?every 6 h for 4 days the ratio was 1.39:1.
Obesity has been reported to increase busulfan clearance. Dosing based on body surface area or adjusted ideal bodyweight should be considered in the obese.
5.3 Preclinical safety data
Busulfan has been shown to be mutagenic in various experimental systems, including bacteria, fungi,?Drosophila?and cultured mouse lymphoma cells.
In vivo?cytogenetic studies in rodents have shown an increased incidence of chromosome aberrations in both germ cells and somatic cells after Busulfan treatment.
There is limited evidence from preclinical studies that Busulfan is carcinogenic in animals (see section 4.4).
There is evidence form animal studies that busulfan produces foetal abnormalities and adverse effects on off-spring, including defects of the musculo-skeletal system, reduced body weight and size, impairment of gonad development and effects on fertility.
Busulfan interferes with spermatogenesis in experimental animals. Limited studies in female animals indicate busulfan has a marked and irreversible effect on fertility through oocyte depletion.
- PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, anhydrous, Pregelatinised starch
Hypromellose, Titanium dioxide, Triacetin
6.3? Shelf life
6.4 Special precautions for storage
Do not store above?25?C
6.5 Nature and contents of container
Busulfan Tablets are packed in Bottle.
Pack Size of: 7, 14, 28, 30, 50, 90, 100 or 200 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Safe handling of Busulfan tablets
The tablets should not be divided and provided the outer coating is intact, there is no risk in handling Busulfan tablets.
Handlers of Busulfan tablets should follow guidelines for the handling of cytotoxic drugs.
Busulfan tablets surplus to requirements should be destroyed in a manner appropriate for the destruction of dangerous substances.
Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).
Busulfan Tablets USP 2mg Taj Pharma
Package leaflet: Information for the patient
Busulfan 2mg tablet
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
?- If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4).
What is in this leaflet
1. What Busulfan is and what it is used for
2. What you need to know before you take Busulfan
3. How to take Busulfan
4. Possible side effects
5. How to store Busulfan
6. Contents of the pack and other information
1.WHAT BUSULFAN IS AND WHAT IT IS USED FOR
Busulfan tablets contain a medicine called busulfan. This belongs to a group of medicines called cytotoxics (also called chemotherapy). Busulfan is used for certain blood problems and cancers of the blood. It works by reducing the number of new blood cells your body makes.
Busulfan is used for:
- Chronic myeloid leukaemia– a disease that increases the number of white blood cells. This can cause infections and bleeding.
- Polycythaemia veraa disease which increases the number of red cells in your blood. This makes the blood thicken and causes blood clots. This leads to headaches, dizziness and shortness of breath.
- Thrombocythaemiaa disease which affects platelets (blood cells which help blood to clot). There may be an increase in platelets – which causes blood clots. Or the platelets do not work properly – which causes bleeding such as nose bleeds, bleeding gums and bruising easily.
- Myelofibrosisa disease where bone marrow (where blood cells are made) is replaced by scar (fibrous) tissue. This causes red and white blood cells to be made wrongly. This can cause tiredness, bloated stomach, bleeding, and bruising.
- Preparing you before?haemopoietic progenitor cell transplantation. This is where blood cells growing in a healthy donor?s bone marrow are transferred to your bone marrow to help you produce healthy cells.
Ask your doctor if you would like more explanation about these diseases.
- WHAT YOU NEED TO KNOW BEFORE YOU TAKE BUSULFAN
Do not take Busulfan if:
- You are allergic (hypersensitive) to busulfan or any of the other ingredients of this medicine (listed in section 6).
- You have taken Busulfan before and it did not work.
Do not take Busulfan if any of the above apply to you.
If you are not sure, talk to your doctor or pharmacist before taking Busulfan.
Warnings and precautions
Talk to?your doctor or pharmacist before taking Busulfan, if:
- You have had radiotherapy, now or recently.
- You have an inherited blood problem called thalassaemia.
- You have ever had gout (painful and swollen joints caused by uric acid crystals). You may need treatment for your gout before you start taking Busulfan.
- You have a liver, kidney or lung problem.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Busulfan.
Other medicines and Busulfan
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This includes herbal medicines.
In particular tell your doctor or pharmacist if you are taking any of the following:
- Other cytotoxic drugs (chemotherapy) – when used with Busulfan there is a greater chance of side effects, such as breathing problems.
- Phenytoin (used to treat and prevent fits) – your doctor may need to change your phenytoin to a different medicine.
- Vaccines which contain live organisms (such as oral polio, measles, mumps and rubella) – Busulfan can make your body less able to fight infections.
- Itraconazole (for fungal infections) or metronidazole (for bacterial infections) – they can cause serious side effects if used with Busulfan.
- Cyclophosphamide (used for certain types of blood disorders) – if used with Busulfan, it is best that your first cyclophosphamide dose is given 24 hours or longer after the last Busulfan dose. This will reduce the chance of any possible side effects.
- An anaesthetic for an operation at the hospital or dentist. If so, tell your doctor or dentist that you are taking Busulfan.
- The use of Paracetamol during Busulfan administration should be used with caution.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. This applies to both men and women. Busulfan may harm your sperm or eggs. Reliable contraceptive precautions must be taken to avoid pregnancy whilst you or your partner are taking these tablets. Ask your doctor for advice.
If you are already pregnant, it is important to talk to your doctor before taking Busulfan.
Do not breast-feed while taking Busulfan. Ask your doctor or midwife for advice.
Busulfan contains lactose
If you have been told by your doctor that you have intolerance to some sugars contact your doctor before taking this medicinal product.
- HOW TO TAKE BUSULFAN
Busulfan should only be given to you by a specialist doctor who is experienced in treating blood problems.
Always take Busulfan exactly as your doctor has told you. It is important to take your medicine at the right times. The label on your pack will tell you how many tablets to take and how often to take them. If the label doesn’t say or if you are not sure, ask your doctor, nurse or pharmacist.
- Swallow your tablets whole with a glass of water.
- Do not break, crush or chew the tablets.
The dose of Busulfan depends on your blood problem or blood cancer (see section 1).
- Your doctor may also change your dose during your treatment, depending on your needs.
- The dose can sometimes be changed if you are over-weight.
- If you take a high-dose of Busulfan, your doctor may also prescribe another medicine called a benzodiazepine. This will help to stop you having a fit.
- When you take Busulfan your doctor will take regular blood tests. This is to check the number of cells in your blood. Your doctor may sometimes change your dose as a result.
Chronic myeloid leukaemia?The usual first dose is up to 4 mg, given as a single dose. Your doctor will then decide on the size of the next doses, based on your weight.
- The treatment is normally a course which lasts for 12 to 20 weeks. You may have more than one course of treatment.
- Some people have to take Busulfan long term. If you have to take it long term, the usual dose is 0.5 mg to 2 mg each day. If your dose is less than 2 mg each day, your doctor might ask you to take tablets only on certain days. Follow your doctor?s instructions carefully.
- Chronic myeloid leukaemia is rare in children and there is no recommended dose of Busulfan.
- The usual dose is 4 to 6 mg each day.
- The course is usually 4 to 6 weeks. This course can be repeated.
- Some people have to take Busulfan long term. If you have to take it long term, the usual dose is 2 to 3 mg each day. Follow your doctor?s instructions carefully.
Myelofibrosis and essential thrombocythaemia
- The usual dose is 2 to 4 mg each day.
Haemopoietic progenitor cell transplantation
- The medicine is usually taken on days 7, 6, 5, 4 and 3 before your transplant day (Imagine your transplant day is day 0, and that you count down the days before).
- Two days before your transplant, you will also get a medicine called cyclophosphamide. The cyclophosphamide should not be given until 24 hours have passed since your last dose of Busulfan.
- Adults? The usual dose is 1 mg per kilogram of your body weight. This is taken every 6 hours.
- Children? The dose is worked out according to the surface area of your body. This is taken every 6 hours.
If you take more Busulfan than you should
If you take more Busulfan than you should, tell your doctor immediately or go to a hospital straight away. Take the medicine pack with you.
If you forget to take Busulfan
Tell your doctor.?Do not take a double dose to make up for a forgotten dose.
4.POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any of the following, talk to your specialist doctor or go to hospital straight away:
- any signs of fever or infection (sore throat, sore mouth or urinary problems)
- any unexpected bruising or bleeding, as this could mean that too few blood cells of a particular type are being produced
- if you?suddenlyfeel unwell (even with a normal temperature)
Talk to your doctor if you have any of the following side effects which may also happen with this medicine:
Very common (affects more than 1 in 10 people)
- a drop in the number of blood cells and platelets
- feeling sick (nausea), being sick (vomiting), diarrhoea and mouth ulcers – with high doses of Busulfan
- yellowing of the whites of the eyes or skin (jaundice) and liver damage – with high doses of Busulfan
- in women, periods may stop, fertility may be affected and the menopause may start early – with high doses of Busulfan
- in girls, the start of puberty may be delayed or prevented
- in boys and men, sperm production may be delayed, reduced or stopped and your testicles may reduce in size
- inflammation of the lung with no sign of infection – called pneumonia syndrome – with high doses of Busulfan
Common (affects less than 1 in 10 people)
- your heart may not be able to beat properly – especially if you have an inherited blood problem called thalassaemia
- inflammation of the lungs which causes breathlessness, cough and raised temperature ? called pneumonitis
- hair loss (with high doses of Busulfan)
- appearance of patches of dark skin
- signs of blood in your urine and pain when passing water (bladder inflammation) – with high doses of Busulfan at the same time as taking a medicine called cyclophosphamide
Uncommon (affects less than 1 in 100 people)
- in women, periods may stop and fertility may be affected and menopause may start early – with usual doses of Busulfan
Rare (affects less than 1 in 1,000 people)
- a severe drop in red blood cells which can cause tiredness, weakness, bruising and make you more likely to get infections ? called aplastic anaemia
- fits or seizures – with high doses of Busulfan
- cataracts or other eye problems – after bone marrow transplantation and with high doses of Busulfan
- feeling or being sick (nausea or vomiting), diarrhoea and mouth ulcers – with usual doses of Busulfan. This can be improved by splitting the dose through the day
- jaundice (yellowing of the whites of eyes or skin) and liver damage – with usual doses of Busulfan
- hair loss (with normal doses of Busulfan)
- dry mouth and lips or other skin changes including very dry skin, itching or rash
Very rare (affects less than 1 in 10,000 people)
- muscle weakness commonly leading to drooping eye lids and difficulty in speaking or using your arms and legs ? called Myasthenia gravis
- enlargement of breasts in men
- weakness, feeling very tired, weight loss, feeling sick, being sick and dark skin patches ? which resembles Addison?s disease (but with the adrenal glands working correctly)
Not known (frequency cannot be estimated from the available data)
- Incomplete development of teeth
Additional side effects reported with intravenous busulfan
Very common (affects more than 1 in 10 people)
- allergic reaction
- decrease in magnesium, calcium, potassium, phosphate and increase in blood sugar
- headache, dizziness, sleeplessness, anxiety and depression
- increase in heart rate
- increase or decrease of blood pressure, dilation of the blood vessels and blood clots
- abdormal pain, heart burn, fluid in the abdomen, constipation, anal discomfort
- enlarged liver
- back, muscle or joint pain
- discomfort in urination, decrease in urine output, increased creatinine in blood
- fever, chills, pain, oedema (swelling from fluid accumulation in body tissues), chest pain
- abnormal breath sounds, weight increased
Common (affects less than 1 in 10 people)
- low blood sodium
- abnormal heart rhythm, enlarged heart, inflammation of the tissue enclosing the heart, decrease heart output
- increase in breath rate, respiratory failure, asthma, collapse of small portions of the lung, fluid around lung
- vomiting blood, decreased movements of the gut, inflammation of the mucosa of oesophagus
- moderate kidney insufficiency, bloody urine, increase in the amount of nitrogen in the blood
Uncommon (affects less than 1 in 100 people)
- cerebral haemorrhage, abnormal brain function
- extra heart beats, decrease in heart rate, clotting of femoral artery, diffuse leak of fluid from the capillaries (small blood vessel)
- bleeding of the stomach and/or the gut
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
- HOW TO STORE BUSULFAN
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the pack after ?Exp?. The expiry date refers to the last day of that month.
- Do not store above 25?C.
- Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how to throw away medicine you no longer use. These measures will help protect environment.
- CONTENTS OF THE PACK AND FURTHER INFORMATION
What Busulfan contain
The active ingredient is busulfan. Each Busulfan tablet contains 2 mg of busulfan.
The other ingredients are lactose anhydrous, pregelatinised starch, magnesium stearate, hypromellose, titanium dioxide and triacetin.
?What Busulfan look like and contents of the pack
Busulfan Tablets are packed in Bottle
Pack Size of: 7, 14, 28, 30, 50, 90, 100 or 200 tablets.
Not all pack sizes may be marketed.
7. Manufactured by:
Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).